Compounds that have retinoid-like activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. The prior art has developed a large number of chemical compounds which have retinoid-like biological activity, and voluminous patent and chemical literature exists describing such compounds.
Unfortunately, compounds having retinoid-like activity (retinoids) also cause a number of undesired side effects at therapeutic dose levels, including headache, teratogenesis, mucocutaneous toxicity, musculoskeletal toxicity, dyslipidemias, skin irritation, headache and hepatotoxicity. These side effects limit the acceptability and utility of retinoids for treating disease.
It is now general knowledge in the art that two main types of retinoid receptors exist in mammals (and other organisms). The two main types or families of receptors are respectively designated the RARs and RXRs. Within each type there are subtypes; in the RAR family the subtypes are designated RARα, RARβ and RARγ, in RXR the subtypes are: RXRα, RXRβ and RXRγ. It has also been established in the art that the distribution of the two main retinoid receptor types, and of the several sub-types, is not uniform in the various tissues and organs of mammalian organisms. Moreover, it is generally accepted in the art that many unwanted side effects of retinoids are mediated by one or more of the RAR receptor subtypes. Accordingly, among compounds having agonist-like activity at retinoid receptors, specificity or selectivity for one of the main types or families, and even specificity or selectivity for one or more subtypes within a family of receptors, is considered a desirable pharmacological property.
For a general overview of the retinoid receptors see Mangelsdorf et al. (1994) The Retinoid Receptors In: The Retinoids, edited by Sporn et al. p 319-349. Raven Press, Ltd., New York. For another general overview see Dawson and William H. Okamura, Chemistry and Biology of Synthetic Retinoids, published by CRC Press Inc., 1990, pages 324-356.
Compounds have also been developed in the art which bind to RAR receptors without triggering the response or responses that are triggered by agonists of the same receptors. The compounds or agents which bind to RAR receptors without triggering a “retinoid” response are thus capable of blocking (to lesser or greater extent) the activity of RAR agonists in biological assays and systems. Such compounds are described, for example, in U.S. Pat. Nos. 5,877,207; 5,952,345 and 5,958,954. As further literature in this field published PCT Application WO 94/14777 is noted that describes certain heterocyclic carboxylic acid derivatives which bind to RAR retinoid receptors and are said in the application to be useful for treatment of certain diseases or conditions, such as acne, psoriasis, rheumatoid arthritis and viral infections. A similar disclosure is made in the article by Yoshimura et al. J. Med. Chem. 38: 3163-3173 (1995). Kaneko et al. Med. Chem. Res. 1:220-225 (1991); Apfel et al. Proc. Natl. Acad. Sci. USA 89: 7129-7133 Augusty 1992 Cell Biology; Eckhardt et al. Toxicology Letters 70:299-308 (1994); Keidel et al. Molecular and Cellular Biology 14:287-298 (1994); and Eyrolles et al. J. Med. Chem. 37: 1508-1517 (1994) describe compounds which have antagonist like activity at one or more of the RAR retinoid subtypes.
“Chalcone moiety” or “chalcone linker” and “chalcone oxime linker” are terms for describing in this application moieties that have the structure shown below
and which in the present invention covalently link two aromatic or heteroaromatic moieties. In the formula the stars indicate the carbons to which the aromatic rings are attached, respectively.
The following references disclose retinoid compounds which are disubstituted “chalcone” compounds: U.S. Pat. Nos. 6,455,701; 6,469,028; 6,225,494; 5,723,666; 5,739,338 and 5,760,276.
PCT Publication WO 02/28810 A2 discloses compounds useful for treating emphysema and associated pulmonary diseases and the general formulas provided in this disclosure include chalcone oxime compounds.
U.S. Pat. Nos. 5,723,666; 5,599,967; and 5,605,915 disclose retinoid compounds which include an oxime moiety.
In addition to undesirable side-effects of therapy with retinoid compounds, there occurs occasionally a serious medical condition caused by vitamin A or vitamin A precursor overdose, resulting either from the excessive intake of vitamin supplements or the ingestion of liver of certain fish and animals that contain high levels of the vitamin. The chronic or acute toxicities observed with hypervitaminosis A syndrome include headache, skin peeling, bone toxicity, dyslipidemias, etc. In recent years, it has become apparent that the toxicities observed with vitamin A analogs, i.e., retinoids, essentially recapitulate those of hypervitaminosis A syndrome, suggesting a common biological cause, i.e., RAR activation. Although some retinoid antagonists are known in the art, the above-noted retinoid-caused toxicities are presently treated mainly by supportive measures and by abstaining from further exposure to the causative agent, whether it is liver, vitamin supplements, or retinoids. While some of the toxicities resolve with time, others (e.g., premature epiphyseal plate closure) are permanent.
Generally speaking, specific antidotes are the best treatment for poisoning by pharmacological agents, but only about two dozen chemicals or classes of chemicals out of thousands in existence have specific known antidotes. Specific antidotes would clearly be of value in the treatment of hypervitaminosis A and retinoid toxicity. Indeed, as increasingly potent retinoids are used clinically, a specific antidote for retinoid poisoning could be life saving. Moreover, because many known retinoids are selective to one more retinoid receptor subtypes, and because of the various biological pathways activated by the different retinoid receptor subtypes, and still further because of the varying distribution of the retinoid subtypes in the mammalian organs, compounds which are antagonists to RARγ receptors, and particularly compounds which are specific or selective antagonists of RARγ receptors are pharmacologically desirable. The present invention provides such compounds.